Social stress accelerates myelopoiesis and shifts erythropoiesis to the spleen

Abstract

In humans, chronic stress is associated with an increased prevalence of mental health complications including anxiety and depression. Repeated social defeat (RSD) in mice recapitulates key deficits associated with psychosocial stress in humans. We have reported that exposure to sub threshold stress 24 days after RSD caused the recurrence of anxiety that was dependent on monocyte trafficking from the spleen to the brain. We hypothesized that extramedullary production of monocytes in the spleen underlies enhanced monocyte trafficking and recurring anxiety following psychosocial stress. Here we show novel data that RSD causes substantial engraftment of hematopoietic stem progenitor cells (HSPCs) in the spleen. For example, RSD significantly increased the presence of all sub-types of progenitor lineages in the spleen, but profoundly increased lineages associated with: Monocytes (M), Granulocytes (G), Granulocytes-Monocytes (GM) and Multipotent Progenitors (GEMM). Moreover, there was a 30-fold increase in the number of Lin-/Sca1+/cKit+ (LSK) progenitor cells in the spleen after stress that were proliferating (S/G2/M cell cycle phase). Next, we tested if these stem cells in the spleen after stress could re-establish the bone marrow of a BM-ablated mouse. In these experiments, mice were subjected to RSD and splenocytes from CD45.1+ mice were co-transferred with GFP+ bone marrow competitor cells into myoablated CD45.2+ mice. Engraftment of donor stem cells was determined 4 months later. There was significant increase in BM engraftment (28-fold) of CD45.1+ splenocytes derived from RSD mice. If extramedullary hematopoiesis was responsible for enhanced monocyte trafficking from the spleen 24 days after RSD, then progenitor proliferation would have to be maintained for this same time period. Even 24 days after RSD, there was a significant increase in the number of splenic CFU, specifically of the GM-CFU subtype. Furthermore, using a BrdU pulse chase experiment, there was significant increase in the number of BrdU+/CD11b+ splenic monocytes in the red pulp 24 days after RSD. These data indicate that RSD caused extramedullary hematopoiesis that resulted in long term monocyte proliferation in the spleen that persisted for at least 24 days.